Abstract 5371: Epigenetic regulation in skin cancer: global DNA methylation profiling in DMBA/TPA induced mice.

Hypermethylation of CpG islands in the promoter regions of tumor suppressor genes is postulated to be the most relevant epigenetic changes resulting in gene silencing of tumor suppressor gene in cancer. Transcriptionally repressed genes by epigenetic regulation can be reactivated by epigenetic modifications because these silenced genes are still genetically intact. Thus, it is relevant to profile global DNA methylation changes that occur in early stages of carcinogenesis (Jones & Baylin, 2002). To begin addressing this issue, we conducted global profiling of DNA methylation changes in a well-established multistage skin carcinogenesis model using methylated DNA immunoprecipitation (Medip) coupled with CpG island microarray. Tumorigenesis was induced by sequential topical application of mutagen 7,12-Dimethylbenz(a)anthracene (DMBA), and promoting agent 12-O-tetra-decanoylphorbol-13-acetate (TPA), on the dorsal skin of normal CD-1 mice. After 12 weeks, animals were sacrificed and DNA extracted from papillomas. Methylation enriched DNA fragments were pulled down and hybridized to CpG microarray covering 16,030 CpG islands (Agilent, Santa Clara, CA) The results show that significant changes in DNA methylation profile between normal skin and DMBA/TPA induced papilloma, analyzed by Genespring and Bioconductor. After normalization of probe with the gene, 186 genes from 9,867 of up-regulated methylation genes showed at least average 2-fold changes and these include some DNA damage and repair, oxidative stress and inflammatory genes such as Gadd45b and Arnt2. In summary, DMBA/TPA induced mouse skin papilloma undergo extensive aberrant CpG island hypermethylation. Genes detected from Medip-chip assay may be utilized as a potential epigenetic tool to study skin cancer. Jones, P. A., & Baylin, S. B. (2002). The fundamental role of epigenetic events in cancer. Nature Reviews Genetics, 3, 415-428. Citation Format: Jong Hun Lee, Limin Shu, Mou-Tuan Huang, Allan H. Conney, Ah-Ng Tony Kong. Epigenetic regulation in skin cancer: global DNA methylation profiling in DMBA/TPA induced mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5371. doi:10.1158/1538-7445.AM2013-5371